Group A streptococcal cell wall (SCW) fragments induce biphasic of chronic inflammation in the LEW, but not the genetically similar F344, rat. In continuing studies to identify the cellular and molecular mechanisms of differential genetic susceptibility, individual cell populations and tissues from the two strains were compared for their responsiveness to SCW in vitro and in vivo. Two inflammatory mediators, TGF-beta and IL-1 have been identified in inflamed synovium and gingiva. A single intraarticular injection of a monoclonal antibody to TGF-beta reduces both the acute and chronic SCW-induced arthrits. Histological analysis revealed a decrease in mononuclear infiltration, and bone and cartilage destruction. In parallel studies, systemic administration of IL-4, which inhibits chronic arthritis, due in part to the induction of IL-1ra, which neutralizes IL-1 activity. Histopathological evaluation confirmed the clinical observations. These studies show that by neutralizing certain pro-inflammatory cytokines, chronic lesions can be suppressed. Additional studies revealed that Kupffer cells are an important source of inflammatory cytokines during SCW-induced hepatic inflammation by expressing and secreting the cytokines TNFalpha, IL- 1beta and TGF-beta. Granuloma formation id dependent, therefore, upon a mechanism of attraction and migration of mononuclear cells. Utilizing another experimental model, studies were performed to investigate the mechanisms involved in the pathogeneisis of chronic intestinal inflammation after a single subserosal injection of SCW/into LEW rats. Collectively, these studies try to elucidate the mechanisms of pathogenesis of chronic, inflammatory diseases.